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Curative-Intent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck in Sri Lanka: The Impact of Radiotherapy Technique on Survival

Published:October 09, 2021DOI:https://doi.org/10.1016/j.clon.2021.09.017

      Highlights

      • A large proportion of patients with SCCHN treated with curative-intent radiotherapy in Sri Lanka had locally advanced disease.
      • Outcomes were superior in patients treated with IMRT in the linear accelerator.
      • Expanding radiotherapy resources by procuring more linear accelerators and better early detection strategies could substantially improve outcomes of the patients.

      Abstract

      Aims

      We conducted a retrospective analysis of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with curative-intent radiotherapy at the National Cancer Institute of Sri Lanka to determine the impact of the treatment technique on disease-free survival (DFS).

      Materials and methods

      SCCHN patients treated with radical radiotherapy or adjuvant postoperative radiotherapy from 2016 to 2017 were included in the study. Data on the following variables were collected by reviewing clinical and radiotherapy treatment records: age, gender, tumour site, stage, time to delivery of radiotherapy, use of neoadjuvant chemotherapy, use of concurrent radiosensitising chemotherapy and treatment technique. DFS, defined as the time to death, tumour recurrence or loss to follow-up, was the primary end point and outcomes were compared between patients treated with intensity-modulated radiotherapy (IMRT) in linear accelerators and those treated with conventional radiotherapy in cobalt teletherapy units. Univariate and multivariate analyses were carried out on known prognostic variables.

      Results

      In total, 408 patients were included in the study, with 138 (34%) being treated with IMRT in the linear accelerator. More than 75% of patients were of stage III or IV at diagnosis. The 2-year DFS of the whole cohort was 25% (95% confidence interval 21–30%). Patients treated with IMRT in the linear accelerator had a superior DFS in comparison with those treated with conventional radiotherapy in the cobalt teletherapy units (P < 0.001, hazard ratio 0.64, 95% confidence interval 0.5–0.82). Higher stage, cobalt treatment and use of neoadjuvant chemotherapy were adversely associated with DFS on multivariate analysis.

      Conclusion

      A large proportion of patients with SCCHN treated with curative-intent radiotherapy in Sri Lanka had locally advanced disease and DFS was superior in patients treated with IMRT in the linear accelerator.

      Key words

      Introduction

      Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer globally, but according to data from the National Cancer Registry in Sri Lanka, it is the most common malignancy in men and the seventh most common among women [
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ,
      • National Cancer Control Programme
      Cancer incidence and mortality data 2015.
      ]. Smoking, alcohol and betel quid chewing are the most common aetiological factors of SCCHN in Sri Lanka, with some evidence to show that infection with human papillomavirus may also be a significant contributor [
      • Gunasekera S.K.
      • Perera K.A.
      • Fernando C.
      • Udagama P.V.
      A shifting paradigm in the aetiology of oral and pharyngeal cancer in Sri Lanka: a case-control study providing serologic evidence for the role of oncogenic HPV types 16 and 18.
      ].
      Although surgery is the primary treatment of choice for cancers of the oral cavity and the sinonasal region, its high morbidity makes radical radiotherapy a much more suitable option for most cases of squamous cell carcinoma of the oropharynx, larynx, hypopharynx and nasopharynx, as it allows tumour control while preserving organ function [
      • Machiels J.P.
      • René Leemans C.
      • Golusinski W.
      • Grau C.
      • Licitra L.
      • Gregoire V.
      Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. The addition of radiosensitising chemotherapy, most commonly with cisplatin, has been shown to improve survival in patients with stage II or higher disease [
      • Pignon J.P.
      • le Maître A.
      • Maillard E.
      • Bourhis J.
      MACH-NC Collaborative Group
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
      ]. Adjuvant postoperative radiation therapy is offered to patients at high risk of developing local recurrence following radical surgery, such as those with close margins and multiple positive lymph nodes [
      • Machiels J.P.
      • René Leemans C.
      • Golusinski W.
      • Grau C.
      • Licitra L.
      • Gregoire V.
      Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ].
      In the curative-intent treatment of SCCHN with radiotherapy, whether as primary radical treatment or in the adjuvant postoperative setting, escalation of the dose delivered to the tumour is limited by the tolerance of adjacent organs at risk, in particular the spinal cord, uninvolved mucosa of the aerodigestive tract and the salivary glands. In addition, the clinical target volumes (CTV) of these patients often take complex concave shapes, especially if the posterior cervical lymph nodes are included. As such, the use of intensity-modulated radiotherapy (IMRT) becomes imperative in the successful curative treatment of most SCCHN, as it ensures that a sufficient dose is delivered to the CTV while sparing dose to organs at risk [
      • Eisbruch A.
      • Foote R.L.
      • O'Sullivan B.
      • Beitler J.J.
      • Vikram B.
      Intensity-modulated radiation therapy for head and neck cancer: emphasis on the selection and delineation of the targets.
      ].
      Cancer treatment is delivered by a network of cancer centres located throughout the country in Sri Lanka's public funded state health service, which is free at the point of delivery [
      • Joseph N.
      • Gunasekera S.
      • Ariyaratne Y.
      • Choudhury A.
      Clinical oncology in Sri Lanka: embracing the promise of the future.
      ]. Radiotherapy services are available in six provincial centres in Sri Lanka, most of which are still delivered using cobalt teletherapy units [
      • Joseph N.
      • Gunasekera S.
      • Ariyaratne Y.
      • Choudhury A.
      Clinical oncology in Sri Lanka: embracing the promise of the future.
      ]. Until recently, Sri Lanka's state health system had only two functional linear accelerators capable of delivering IMRT, both of which were housed at the National Cancer Institute, near the capital city of Colombo [
      • Joseph N.
      • Gunasekera S.
      • Ariyaratne Y.
      • Choudhury A.
      Clinical oncology in Sri Lanka: embracing the promise of the future.
      ]. Scarcity of resources would inevitably mean that only a proportion of patients with SCCHN could be treated with IMRT in the linear accelerators, with most patients being treated with conventional radiotherapy in cobalt teletherapy units [
      • Joseph N.
      • Gunasekera S.
      • Ariyaratne Y.
      • Choudhury A.
      Clinical oncology in Sri Lanka: embracing the promise of the future.
      ].
      We conducted a retrospective analysis of patients with SCCHN treated with curative-intent radiotherapy at the National Cancer Institute of Sri Lanka between 2016 and 2017 to determine the impact of the treatment technique on disease-free survival (DFS).

      Materials and Methods

       Study Population

      Patients with SCCHN treated with radical radiotherapy or adjuvant postoperative radiotherapy at the National Cancer Institute from 2016 to 2017 were included in the study. Patients with a second primary tumour outside the head and neck region were excluded from the study. Patients with systemic metastases and those treated with palliative intent were also excluded, as were those receiving salvage radiotherapy for tumour recurrences following previous radical surgery.

       Diagnosis and Staging

      All patients underwent panendoscopy and biopsy of the primary lesion and fine needle aspiration cytology of suspicious lymph nodes. A computed tomography scan of the head, neck and chest was carried out, but positron emission tomography scans were not available during the study period. Patients with supraglottic, oropharyngeal and hypopharyngeal tumours underwent examination under anaesthesia for further characterisation of the primary tumour.

       Treatment Details

       Primary Radiotherapy

      Patients treated in the cobalt teletherapy units were treated to a total dose of 60–66 Gy in 30–33 fractions over 6–6.5 weeks in two phases using X-ray-based conventional fields. Phase I treatment was delivered using two lateral parallel-opposed fields to the head and neck with an additional matched anterior neck field (if treatment of the lower neck and supra-clavicular fossa was required) to a dose of 40–44 Gy. Phase II treatment comprised two lateral parallel opposed head and neck fields with the posterior border placed anterior to the spinal cord and brainstem and was delivered to an additional dose 20–26 Gy. Patients treated in the cobalt teletherapy units did not receive a posterior photon-based conformal or electron boost, as both of these techniques require treatment in a linear accelerator and access to it was severely limited.
      All patients treated in the linear accelerator were treated with IMRT. The gross tumour volume (GTV) was defined using clinical examination and imaging findings. The high-risk CTV for the primary tumour was derived by adding a customised 5–10 mm margin to the GTV. The high-risk nodal CTV was obtained by adding a 10 mm margin to the nodal GTV and was extended to include the entire nodal station as defined by the DAHANCA/EORTC international consensus guidelines [
      • Grégoire V.
      • Ang K.
      • Budach W.
      • Grau C.
      • Hamoir M.
      • Langendijk J.A.
      • et al.
      Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines.
      ]. A low-risk elective CTV was also contoured in these patients, which comprised uninvolved nodal groups in levels I–V, based on the above guidelines. Treatment in the linear accelerator comprising five to seven static field inverse-planned IMRT was delivered using dynamic multileaf collimators with the sliding window method. Patients treated with IMRT in the linear accelerator received one of two fractionation regimens: 65 Gy in 30 fractions over 6 weeks or 70 Gy in 35 fractions over 7 weeks to the high-risk planning target volume. The low-risk elective nodal planning target volume received either 54 Gy in 30 fractions over 6 weeks or 56 Gy in 35 fractions over 7 weeks.
      Patients were selected for treatment in the cobalt teletherapy units or with IMRT in the linear accelerator, based on availability of slots at the time of registration. As only two linear accelerators were in operation in the institute during the study period, access to it was severely limited. If no slots were available for treatment with IMRT in the linear accelerator and delay was deemed unacceptable, patients received conventional radiotherapy in the cobalt teletherapy units.

       Postoperative Radiotherapy

      One or more of the following factors was the indication for adjuvant postoperative treatment: close (<5 mm) or positive margins, T3 or higher tumour stage, multiple involved lymph nodes or a solitary involved lymph node with extranodal extension. In postoperative patients treated with IMRT in the linear accelerator, the CTV comprised the tumour bed with a 10 mm margin for the primary tumour and level I–V lymph nodal regions in patients with node-positive tumours. Patients treated in the cobalt units were treated with a conventional X-ray anatomy-based two-phase technique as described above. The dose prescription in this setting was identical for patients treated with IMRT in the linear accelerator and in the cobalt units – 66 Gy in 33 fractions over 6.5 weeks in patients with positive margins or extranodal extension, whereas patients without these features received a dose of 60 Gy in 30 fractions over 6 weeks.

       Concurrent Chemotherapy

      Concurrent radiosensitising chemotherapy, comprising intravenous weekly cisplatin at a dose of 40 mg/m2 was offered to fit patients treated with radical radiotherapy with stage II or higher disease, as well as to those receiving adjuvant postoperative radiotherapy if margins were positive or extranodal tumour extension was present. Patients with impaired renal functions and those deemed unfit for concurrent chemoradiotherapy were treated with radiotherapy alone.

       Neoadjuvant Chemotherapy

      Some patients with locally advanced disease were offered two cycles of neoadjuvant chemotherapy, which comprised intravenous cisplatin 75 mg/m2 delivered on day 1 together with a continuous infusion of intravenous 5-fluorouracil 750–1000 mg/m2 delivered on days 1–4 with a second cycle delivered after 21 days.

       Data Collection

      Data on the following variables were collected by reviewing clinical and radiotherapy treatment records: age, gender, tumour site, stage, primary treatment, time to delivery of radiotherapy, use of neoadjuvant chemotherapy, use of concurrent radiosensitising chemotherapy and treatment technique.

       Analysis

      The distribution of clinicopathological variables between patients treated with IMRT in the linear accelerator and cobalt teletherapy units was compared using the Mann–Whitney U-test for continuous variables and the chi-squared test for categorical variables.
      For analysis of survival, in keeping with the guidelines of the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project, we considered DFS, defined as the time to death or tumour recurrence, as the primary end point [
      • Bellera C.A.
      • Pulido M.
      • Gourgou S.
      • Collette L.
      • Doussau A.
      • Kramar A.
      • et al.
      Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints' definitions in cancer clinical trials.
      ]. In addition, we considered loss to follow-up as an event to avoid overestimation of survival, as the overwhelming probabilities are that these patients experienced an event. Survival analysis was carried out using the Kaplan–Meier method with the Log-rank test used to determine the difference in survival between patients treated with IMRT against those treated in the cobalt teletherapy units.
      Univariate analysis was carried out for the following prognostic factors using the Log-rank test for categorical variables and the univariate Cox proportional hazards test for continuous variables: age, gender, tumour site, stage, use of neoadjuvant chemotherapy, use of concurrent radiosensitising chemotherapy and time to initiation of radiotherapy. Factors significant on univariate analysis were included in a multivariate Cox proportional hazards model.

      Results

      In total, 408 patients were included in the study, with 138 (34%) of them being treated with IMRT in the linear accelerator. Table 1 lists the distribution of clinicopathological variables of the whole population and by treatment technique (IMRT in the linear accelerator versus conventional radiotherapy in the cobalt teletherapy unit).
      Table 1Comparison between patients treated with intensity-modulated radiotherapy (IMRT) in the linear accelerator and with conventional radiotherapy in the cobalt-60 units
      VariableWhole study population n = 408IMRT n = 138Cobalt 60 n = 270Significance (P value)
      Age (Median, IQR in years)60 (53–68)58 (48–65)62 (54–69)<0.001
      Gender (female)59 (14%)29 (21%)30 (11%)0.01
      Site

      Oral cavity

      Oropharynx

      Larynx

      Hypopharynx

      Nasopharynx

      Other
      139 (34%)

      111 (27%)

      77 (19%)

      42 (10%)

      13 (3%)

      26 (6%)
      50 (36%)

      31 (22%)

      16 (12%)

      8 (6%)

      13 (9%)

      20 (14%)
      89 (33%)

      80 (30%)

      61 (23%)

      34 (12%)



      6 (2%)
      <0.001
      Stage

      I

      II

      III

      IV

      Not available
      32 (8%)

      63 (16%)

      116 (30%)

      177 (46%)

      20 (5%)
      12 (9%)

      21 (16%)

      41 (31%)

      57 (44%)

      7 (5%)
      20 (8%)

      42 (16%)

      75 (29%)

      120 (47%)

      13 (5%)
      0.58
      Time to start of radiotherapy in days

      Median (IQR)
      31 (19–68)77 (55–131)24 (14–33)<0.001
      Postoperative radiotherapy79 (19%)46 (33%)33 (12%)<0.001
      Neoadjuvant chemotherapy70 (17%)46 (33%)24 (9%)<0.001
      Concurrent chemoradiotherapy223 (55%)56 (41%)167 (62%)<0.001
      Concurrent chemotherapy compliance (proportion completed all cycles)184 (83%)49 (88%)135 (81%)0.26
      Radiotherapy treatment interruptions39 (10%)10 (7%)29 (11%)0.25
      Rate of completion of full treatment course16 (4%)4 (3%)12 (4%)0.44
      IQR, interquartile range.
      Patients treated with IMRT were of a slightly younger age group (median age 58 versus 62 years) and had a higher proportion of postoperative cases (33% versus 12%). There was, however, a significant delay in the time to initiation of treatment of patients in comparison with those treated in the cobalt units (77 days versus 24 days, P < 0.001). There was no difference in the distribution of stage at diagnosis between the two groups, although more than 75% of patients in the whole cohort were stage III and IV. Neoadjuvant chemotherapy was delivered in 70 (17%) patients, whereas 223 (55%) patients received concurrent chemotherapy, with 36 (9%) patients receiving both neoadjuvant and concurrent chemotherapy. The use of neoadjuvant chemotherapy was also more frequent in the IMRT group but use of concurrent chemoradiotherapy was more common in the cobalt cohort. There was no difference in treatment interruptions, the proportion completing the full course of radiotherapy or compliance with concurrent chemotherapy between the two groups, as shown in Table 1.
      There were 319 (78%) events in the whole study population, with 72 (18%) deaths, 188 (46%) confirmed recurrences and 59 (14%) cases of loss to follow-up. Locoregional recurrence comprised 160 of 188 recurrences (85%), whereas there were 20 (11%) cases of distant metastases and eight (4%) new primary squamous cell tumours in the head and neck region. Supplementary Table S1 gives a detailed breakdown of events in the IMRT and cobalt cohorts separately. The median follow-up for the whole cohort was 8 months, interquartile range 3–13. The median follow-up of censored patients was 34 months, interquartile range 27–39.
      The 2-year DFS of the whole cohort was 25% (95% confidence interval 21–30%), as illustrated in Figure 1. As shown in Figure 2, patients treated with IMRT had a superior DFS in comparison with those treated in the cobalt teletherapy units (P < 0.001, hazard ratio 0.64, 95% confidence interval 0.5–0.82). The 2-year DFS was 39% (95% confidence interval 32–48%) for patients treated with IMRT in comparison with 18% (95% confidence interval 14–23%) for those treated in the cobalt teletherapy units.
      Fig 1
      Fig 1Disease-free survival of the whole cohort.
      Fig 2
      Fig 2Disease-free survival by treatment technique.
      As shown in Table 2, higher stage, treatment in cobalt 60 units and use of neoadjuvant chemotherapy were adversely associated with DFS on multivariate analysis. Fig 3, Fig 4 depict DFS by stage and neoadjuvant chemotherapy, respectively. Patients with laryngeal tumours had the best survival, whereas patients with hypopharyngeal tumours had the poorest survival. However, the prognostic significance of the tumour site was not sustained in the multivariate analysis.
      Table 2Univariate and multivariate analysis of prognostic factors
      VariableUnivariate analysisMultivariate analysis
      AgeP = 0.32
      GenderP = 0.25
      SiteP = 0.004

      Hypopharynx HR 1.61 (CI 0.99–2.6)

      Larynx HR 0.71 (CI 0.44–1.12)

      Oral HR 1.07 (CI 0.7–1.61)

      Oropharynx HR 1.05 (CI 0.69–1.61)
      P = 0.51
      StageP < 0.001

      HR 1.55 (CI 1.36–1.77)
      P < 0.001

      HR 1.48 (CI 1.29–1.7)
      Treatment technique (IMRT)P < 0.001

      HR 0.64 (CI 0.5–0.82)
      P < 0.001

      HR 0.56 (CI 0.42–0.76)
      Neoadjuvant chemotherapy0.003

      HR 1.53 (CI 1.16–2.02)
      P = 0.02

      HR 1.49 (CI 1.05–2.1)
      Concurrent chemoradiotherapyP = 0.59
      Time to start of radiotherapyP = 0.09
      CI, 95% confidence interval; HR, hazard ratio; IMRT, intensity-modulated radiotherapy.
      Fig 4
      Fig 4Disease-free survival by use of neoadjuvant chemotherapy.

      Discussion

      Here we report the outcomes of patients with SCCHN in Sri Lanka, which show a clear superiority of DFS in patients treated with IMRT in linear accelerators in comparison with those treated with conventional radiotherapy in the cobalt teletherapy units. The superior DFS of patients treated with IMRT was in spite of the fact that most of these patients had waiting times in excess of 2 months to receive their treatment in comparison with those treated in cobalt units.
      There are some data to suggest that outcomes are similar in patients with early laryngeal tumours treated in the cobalt teletherapy units in comparison with treatment in the linear accelerators [
      • Krstevska V.
      • Stojkovski I.
      • Zafirova-Ivanova B.
      Radical radiotherapy for squamous cell carcinoma of the larynx – comparison of three-dimensional conformal radiotherapy with cobalt-60 teletherapy.
      ]. However, in most other tumours, the complexity of the CTV means that a curative dose cannot be delivered without compromising dose to the critical organs at risk, especially the spinal cord, using conventional radiotherapy [
      • Eisbruch A.
      • Foote R.L.
      • O'Sullivan B.
      • Beitler J.J.
      • Vikram B.
      Intensity-modulated radiation therapy for head and neck cancer: emphasis on the selection and delineation of the targets.
      ].
      Even after accounting for the stage at presentation, the overall DFS of the whole cohort is less than that reported in the Western world [
      • Tiwana M.S.
      • Wu J.
      • Hay J.
      • Wong F.
      • Cheung W.
      • Olson R.A.
      25 year survival outcomes for squamous cell carcinomas of the head and neck: population based outcomes from a Canadian province.
      ]. Although coverage of the tumour volume would have been compromised in patients treated in the cobalt units, long delays in initiating treatment would have contributed to a lower survival in the IMRT group [
      • Fowler J.F.
      21 years of biologically effective dose.
      ,
      • Withers H.R.
      • Maciejewski B.
      • Taylor J.M.
      • Hliniak A.
      Accelerated repopulation in head and neck cancer.
      ]. Patients receiving primary radiotherapy with IMRT received a slightly higher biological dose with the 65 Gy in 30 fractions over 6 weeks regimen in comparison with patients treated in the cobalt teletherapy units who received a dose of 66 Gy in 33 fractions over 6.5 weeks, which may have contributed to the superior outcome in the IMRT cohort. The IMRT cohort also had a higher proportion of patients receiving postoperative radiotherapy. As the primary treatment had already been completed, the urgency to initiate radiotherapy may have been less of an imperative in these patients and as such clinicians would have been more likely to accept the long waiting time for treatment with IMRT. Moreover, concerns of increased toxicity with treatment in the cobalt units in patients after radical surgery may have also been a contributory factor.
      The Lancet Commission on Global Access to Radiotherapy [
      • Atun R.
      • Jaffray D.A.
      • Barton M.B.
      • Bray F.
      • Baumann M.
      • Vikram B.
      • et al.
      Expanding global access to radiotherapy.
      ] estimates that radiotherapy would lead to an absolute improvement of 34% in local control of SCCHN. Although there are a number of confounding factors between patients treated with IMRT in the linear accelerator and those treated in the cobalt units, our findings provide robust real-world data to further confirm that investment in modern radiotherapy technology would translate into improved survival. Our results highlight the importance of procuring and commissioning more linear accelerators capable of delivering IMRT in Sri Lanka, as well as the imperative need for a more concerted effort, at a global level to raise awareness of the cost-effectiveness and curative potential of radiotherapy in resource-limited settings [
      • Joseph N.
      • Gunasekera S.
      • Ariyaratne Y.
      • Choudhury A.
      Clinical oncology in Sri Lanka: embracing the promise of the future.
      ,
      • Gospodarowicz M.
      Global access to radiotherapy-work in progress.
      ].
      Undoubtedly, much progress has been made in the quest for greater biological and anatomical precision in radiotherapy with the advent of new technologies such as proton beam therapy and the magnetic resonance imaging-based linear accelerator [
      • Blanchard P.
      • Gunn G.B.
      • Lin A.
      • Foote R.L.
      • Lee N.Y.
      • Frank S.J.
      Proton therapy for head and neck cancers.
      ,
      • de Mol van Otterloo S.R.
      • Christodouleas J.P.
      • Blezer E.L.A.
      • Akhiat H.
      • Brown K.
      • Choudhury A.
      • et al.
      The MOMENTUM study: an international registry for the evidence-based introduction of MR-guided adaptive therapy.
      ]. However, these developments must not cast a shadow on improving global access to radiotherapy in resource-limited settings, which can be achieved by procuring less sophisticated linear accelerator units that are capable of delivering IMRT [
      • Gospodarowicz M.
      Global access to radiotherapy-work in progress.
      ].
      There are a number of other sobering findings in our study that also need emphasis. First is the large proportion of patients with stage III and IV disease in the study cohort, which is common to many cancers in Sri Lanka [
      • Balawardena J.
      • Skandarajah T.
      • Rathnayake W.
      • Joseph N.
      Breast cancer survival in Sri Lanka.
      ,
      • Joseph N.
      • Jayalath H.
      • Balawardena J.
      • Skandarajah T.
      • Perera K.
      • Gunasekera D.
      • et al.
      Radical external-beam radiotherapy in combination with intracavitary brachytherapy for localized carcinoma of the cervix in Sri Lanka: is treatment delayed treatment denied?.
      ]. Although the inclusion criteria would have meant that patients with stage I and II tumours of the oral cavity and tonsil treated with radical surgery alone were excluded from the study, the high proportion of patients with locally advanced disease suggest that more robust early detection strategies in SCCHN are required by increasing public awareness and streamlining diagnostic care pathways.
      Another interesting finding was the adverse survival outcomes of patients treated with neoadjuvant chemotherapy in our cohort. Neoadjuvant chemotherapy was offered to patients with locally advanced (stage III, IV) disease based on clinician discretion and the confounding effect of stage may not have been completely eliminated in the multivariate analysis. However, the higher proportion of patients treated with neoadjuvant chemotherapy in the IMRT cohort does suggest that it may have also been used as a strategy of mitigating delays in initiating treatment. This seems to have diluted the benefit derived from a better treatment technique as suggested by the numerically superior hazard ratio in favour of IMRT in the multivariate analysis, as opposed to the univariate analysis (univariate hazard ratio 0.64, confidence interval 0.5–0.82 versus multivariate hazard ratio 0.56, confidence interval 0.42–0.76). As this was a retrospective analysis, it was not possible to delve further on these aspects, but it is long established that accelerated repopulation is one of the most significant causes of treatment failure in SCCHN, and our data suggest that neoadjuvant chemotherapy should not be routinely offered [
      • Pignon J.P.
      • Bourhis J.
      • Domenge C.
      • Designé L.
      Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer.
      ,
      • Haddad R.I.
      • Posner M.
      • Hitt R.
      • Cohen E.E.W.
      • Schulten J.
      • Lefebvre J.L.
      • et al.
      Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.
      ].
      There are a number of limitations in our study, inherent in a retrospective analysis of this nature, such as the inability to determine the accurate cause of death in some patients together with a significant proportion of patients with loss to follow-up. Nevertheless, it provides real-world evidence of the curative potential of advanced radiotherapy techniques in SCCHN.

      Conclusion

      A large proportion of patients with SCCHN treated with curative-intent radiotherapy in Sri Lanka had locally advanced disease and outcomes were superior in patients treated with IMRT in the linear accelerator. Expanding radiotherapy resources by procuring more linear accelerators and better early detection strategies could substantially improve outcomes of SCCHN patients in Sri Lanka.

      Data Availability

      Data supporting the findings of this study are available from the corresponding author upon request.

      Conflict of interest

      The authors declare no conflicts of interest.

      Funding

      This work did not receive any specific funding from any governmental, private or non-governmental institution.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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